This application requests continued support for a National Cooperative Program in Infertility Research. The focus of this Center will be on the elucidation of the genetic basis of polycystic ovary syndrome (PCOS) and the development of novel therapeutic strategies to restore fertility. The Center will support an interactive and multidisciplinary research program including investigators from the University of Pennsylvania, Northwestern University, and the Pennsylvania State University Milton S. Hershey Medical Center. The multi-faceted program will apply state-of-the-art techniques in molecular genetics, molecular and cell biology, and clinical phenotyping to elucidate susceptibility genes and establish genotype-phenotype relationships. A second goal of the Center is to translate information on PCOS genes into infertility therapy. The major hypothesis underlying the proposed research is that PCOS is caused by variant alleles at one or several loci that cause intrinsic defects in androgen biosynthesis (ovarian and adrenal) but also result in dysfunction of other cell types including skeletal muscle, adipose tissue and the endometrium. The working model is that allelic variants alter signal transduction mechanisms and that pharmacological agents targeting these signal transduction pathways can create PCOS phenocopies as well as reverse the biochemical and molecular phenotype of PCOS. These hypotheses will be addressed by complementary strategies: 1) Intensive clinical phenotyping of PCOS families to identify subtypes and the "male PCOS phenotype"; 2) A molecular genetic approach to the identification of PCOS-related genes based on a candidate gene approach with the long-term goal of a genome-wide linkage analysis; 3) Correlation of genotype and phenotype; 4) Identification of distinguishing biochemical and molecular phenotypes of PCOS cells from an analysis of differential gene and protein expression; and 5) In vitro testing of hypotheses generated from transcript and protein expression profiling. The Center will be a resource for research training and career development, building on a documented tradition of mentorship. The Center's educational mission will include active participation in lay and professional organizations addressing infertility and PCOS.